Extensive evidence indicates that arachidonic acid metabolism, which includes the prostaglandins, hydroperoxyfatty acids and the leukotrienes, may play an essential role in skin carcinogenesis. We have previously observed that specific prostaglandins have a modifying role in tumor promotion. Based in part on recent tumor promotion studies using inhibitors of particular pathways of arachidonic acid transformation, we propose here that the lipoxygenase pathway may be much more critical with respect to promotion than the prostaglandin synthetase pathway, and that inhibitors of this pathway represent a means by which tumor promotion may be inhibited. We plan to test this hypothesis by: (1) identifying and quantitating the arachidonic acid products in mouse skin in response to single, as well as multiple, treatments of the complete tumor promoter 12-0-tetradecanoylphorbol-13-acetate (TPA) and the first and second stage promoters, the ionophore A23187 and mezerein, respectively, or non-promoting hyperplasiogenic agents; (2) determining whether specific lipoxygenase products, i.e., particular hydroperoxyfatty acids or the leukotrienes as first identified in the above metabolism studies, have the ability to modify or replace TPA in single or multistage promotion experiments; and determining the effect of inhibitors specific for various parts of the arachidonate pathway on tumor promotion; (3) determining whether the differences in response to either TPA promotion or the cyclooxygenase inhibitors indomethacin between strains of mice (SENCAR, NMRI, and C57BL/6) are due to strain differences in the metabolism of arachidonic acid. It should be of considerable value to elucidate the role of arachidonic acid metabolites, especially the lipoxygenase products, in skin tumor promotion since it appears that at least some of the metabolites of arachidonic acid are required for full expression of tumor promotion. The studies proposed here should provide insight into these critical and rate-limiting events and may provide some understanding of differing sensitivities between strains of mice.